The mechanism of drug and hormone action on glycogenolysis and contractile function is being investigated in skeletal and cardiac muscle. The relative roles and interactions of cyclic AMP and Ca2 ion as second messengers in regulationg phosphorylase a formation by isoproterenol is being studied in isolated hemidiaphragms incubated in an oxygenated Krebs-Ringer bicarbonate buffer utilizing muscles from one strain of mice. Further studies will extend these investigations to the differences in mechanisms among pharmacogenetic variants carried in inbred strains of mice that differ in their EC50 (concentration given one-half maximum response) or in their maximum response for isoproterenol-stimulated phosphorylase b to a c conversion. In mice of strains that differ in isoproterenol-stimulated cyclic AMP formation, the binding of the radioactive ligand, 125I-iodohydroxybenzylpindolol, to beta-adrenergic receptors in intact muscle will be compared and the coupling-efficiency of the drug-receptor complex with adenylate cyclase will be estimated. The actions of cyclic AMP and Ca2 ion in regulating isoproterenol stimulation of phosphorylase a formation and contractile force is also being studied in isolated right ventricle strips contracting isometrically. These studies will, thus, elucidate important information on the mechanisms of beta-adrenergic responses in intact mammalian skeletal and cardiac muscles and the nature of genetic variation in these responses.